Neurodegenerative diseases are progressive diseases to cause destructive injuries such as the nerve cell death. As principal neurodegenerative diseases, there have been known central nervous diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Hantington's disease, and the like and peripheral neuropathies such as typically diabetic neuropathy. Many of them relate to aging and, in fact, the onset increases with aging, whereas there is a case in which the onset begins even at a middle age and further at a younger age.
As a result of studies on the structure and function of brains, the roles of neurotransmitters and neurotrophic factors and so on have been gradually elucidated, but many parts of the causes of neurodegeneration are still unknown. Only for Parkinson's disease, the relation between it and a specific neurotransmitter, namely dopamine, has been clarified, whereby L-dopa that is the precursor of dopamine has been used as a drug for reducing the nervous symptoms and for recovering the function. However, L-dopa does not suppress the progress of neurodegeneration, and the effect of L-dopa is gradually lost with a progress of the disease condition, namely the degeneration and deficiency of dopamine-based nerve cells. Also, Alzheimer's disease is a disease that is caused by the degeneration and deficiency of a variety of nerve cells such as acetylcholine-based nerve cells, monoamine-based nerve cells, and the like and, as for the drugs therefor, cholinesterase inhibitors have been marketed or under development. Nevertheless, like L-dopa for Parkinson's disease, they are still within the region of symptomatic therapy to improve the nerve symptoms temporarily.
Thus, there has not been reported up to the present time any drug that protects nerve cells from the toxicity of factors causing cell death thereby suppressing the progress of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
Moreover, it is said that the cell death in neurodegenerative diseases is caused by the toxicity of the factors that are intrinsic to the respective diseases and, for example, in Alzheimer's disease, the endogenous β-amyloid is considered to be a factor to cause the cell death. β-Amyloid is a protein constituting the senile plaque, which is a neuropathological characteristic to be seen in brain of a patient suffering from Alzheimer's disease, and is composed of 40 to 43 amino acids. It has been elucidated that the addition of this β-amyloid to a primary culture of hippocampus nerve cell causes nerve cell death [Science, Vol. 245, pp. 417-420 (1989)] and, also, it has been shown that the coagulation of β-amyloid is indispensable for the expression of its toxicity and the like [Neurobiology of Aging, Vol. 13, pp. 587-590 (1992) and Journal of Molecular Biology, Vol. 218, pp. 149-163 (1991)]. For toxicity expression mechanism of β-amyloid, there have been conceived that 1) β-amyloid forms an ion channel to allow an inflow of calcium ions, 2) β-amyloid accelerates generation of free radicals, 3) β-amyloid activates tau protein kinase I (TPK-I) to promote the phosphorylation of tau, 4) β-amyloid activates the microglia, from which the neurotoxin is secreted, and the like.
Recently, it has been elucidated that neurotrophic factors such as IGF-1 (insulin-like growth factor), NGF (nerve growth factor), and the like inhibit the apoptosis of nerve cells by β-amyloid and the like, and that, as the mechanism thereof, inhibition of TPK-I/GSK-3β (glycogen synthetase kinase 3) by activation of PI-3 kinase is concerned in the apoptosis inhibition [Journal of Neuroscience (J. Neurosci.), Vol. 11, pp. 2552-2563 (1991), Science, Vol. 267, pp. 2003-2005 (1995), and The Journal of Biological Chemistry (J. Biol. Chem.), Vol. 272, 154-161 (1997)]. When PI-3 kinase is inhibited by β-amyloid and TPK-I/GSK-3β is activated, pyruvate dehydrogenase (PDH) is inhibited, thereby affecting the synthetic reaction system of acetylcholine to lower the content of acetylcholine. This fact agrees with an observation that the content of acetylcholine is lowered in brain of a patient suffering from Alzheimer's disease. On the contrary, it is expected that the activation of PI-3 kinase results in not only the prevention of nerve cell death but also an increase in the content of acetylcholine in brain, thereby improving the nerve symptoms. In addition, it can be expected that inhibition of TPK-I/GSK-3β increases the intracerebral glucose utilization, which is lowered in Alzheimer's disease [The Journal of Biological Chemistry (J. Biol. Chem.), Vol. 269, 3568-3573 (1994) and Endocrinology, Vol. 125, pp. 314-320 (1989)].
Further, the following compounds have been reported as compounds having a fused nitrogen-containing heterocyclic group on benzene ring that is fuzed with furan ring or dihydrofuran ring.
1) As compounds having an inhibitory activity of bone resorption and bone metabolism, compounds that are represented by the formula:
wherein R1 is hydrogen, lower alkyl, acyl, amino, acylamino, nitro, halogen or hydroxy-lower alkyl that may have one or more appropriate substituents;    R2 is hydrogen, lower alkyl, acyl, lower alkoxy, acyl-lower alkyl, aryl, cyano, mono- (or di- or tri-) halo-lower alkyl, lower alkylthio or hydroxy-lower alkyl that may have one or more appropriate substituents;    R3 is hydrogen, lower alkyl, lower alkenyl, cyclo lower alkyl-lower alkyl, halogen, acyl, acyl-lower alkyl, acylamino, acylamino-lower alkyl, acyl-lower alkenyl, acyloxy-lower alkyl, acyl-lower alkylthio-lower alkyl, amino-lower alkyl, mono- (or di-) lower alkylamino, lower alkylthio-lower alkyl, hydroxyimino-lower alkyl that may have one or more appropriate substituents, hydroxy-lower alkyl that may have one or more appropriate substituents, hydroxy-lower alkylthio-lower alkyl, cyano-lower alkyl, mono- (or di-) lower alkoxyower alkyl that may have one or more appropriate substituents, lower alkyl substituted with aryl that may have one or more appropriate substituents, mono- (or di-) lower alkylamino-lower alkyl, lower alkyl substituted with a heterocyclic group that may have one or more appropriate substituents, a heterocyclic group that may have one or more appropriate substituents, heterocyclic thio, heterocyclic thio-lower alkyl, heterocyclic oxy, heterocyclic oxy-lower alkyl, heterocyclic aminoimino-lower alkyl, aryl, amino or nitro;    R2 and R3 may be combined each other to form a group of    (1) lower alkylene that may have one or more appropriate substituents,    (2) lower alkenylene that may have one or more appropriate substituents, or    (3) the formula: -(A1)m-W-(A2)n-, wherein each of A1 and A2 is lower alkylene that may have one or more appropriate substituents or lower alkenylene that may have one or more appropriate substituents, W is —S—, —S(O)— or —N(R5)— (wherein R5 is hydrogen, lower alkyl or acyl), and each of m and n is an integer of 0 or 1;    X is O or S, Y is vinylene or a group represented by the formula: —NHCO—, —NHSO2—, —OCO—, —OCH2—, —NHCOCO—, —NHCOCH═CH—, —NHCOCH2—, —NHCONH— or —N(R6)CO— (wherein R6 is lower alkyl); Z is a heterocyclic group that may have one or more appropriate substituents or aryl that may have one or more appropriate substituents; l is an integer of 0 or 1; and  represents a single bond or a double bond, and pharmaceutically acceptable salts thereof, and specifically,
(WO 95/29907 and JP 9-512795 A).
2) As compounds having an inhibitory activity of lipid peroxide formation, 3,5-dihydroxyheptanoic acid derivatives represented by the formula:
wherein R1 is hydrogen, nitro, a group represented by —N(R4)R5, wherein each of R4 and R5 is hydrogen, lower alkyl, lower alkenyl, aryl, aralkyl, acyl, aroyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted thiocarbamoyl, or R4 and R5 together may form cyclic amino; each of R2 and R3 is hydrogen or lower alkyl], and 3,5-dihydroxyheptanoic acid derivatives represented by the formula:
wherein R1 is hydrogen, nitro, a group represented by —N(R4)R5, wherein each of R4 and R5 is hydrogen, lower alkyl, lower alkenyl, aryl, aralkyl, acyl, aroyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted thiocarbamoyl group, or R4 and R5 together may form cyclic amino; each of R2 and R3 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, alkali metal or alkaline earth metal (JP 5-194466 A).
3) As herbicides, compounds represented by the formula:
wherein R is H, Cl, F, C1-C2 alkyl or C1-C2 alkoxy; R1 is H, F, Cl, Br, CH3, OCH3, CN, CF3, OCF3 or OCF2H; X1 is 0; R2 is H, CH3 or CH2CH3; R3 is H, C1-C4 haloalkyl, CR2R7CN, CN, CR2R4R7, COCl, COR4, C(NOR6)R2, CO2R4, CONR4R2, CHR2OH, CO2(CH2)2Si(CH3)3, CONR2SO2CH3, CHR2CO2R4, CONHCH(CH3)CONHCH(CH3)CO2CH3, CHR2COR4, CHR2OSO2(C1-C4 alkyl), CHR2OC(O)R4, CHR2OC(O)N(R2)2, CHR2OC(O)N(R2)OCH3, CHR2OC(O)N(R2)Ph, HC═CH2 or C≡CH; R4 is H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C3-C6 alkynyl, C2-C4 haloalkenyl, phenyl, C1-C4 alkylphenyl, C3-C6 alkoxycarbonylalkyl or (CH2CH2O)bR2; b is 1 to 6; m is 1, n is 1 or 2; J is
(wherein X and Y are O or S, respectively), etc. (U.S. Pat. No. 4,881,967).
4) As compounds having an antibacterial activity, compounds represented by the formula:
wherein each of m and n is 0 or 1 and the sum of m and n is 1; R is hydrogen or lower alkyl; R′ is R,
or R and R′ together form (CH3)2N—N═,
or form pyrrole or pyrrolidine; R″ is R, lower alkyl, CF3—, or ClCH2—; and R′″ is lower alkyl or CF3—, or pharmacologically acceptable salts thereof (U.S. Pat. No. 4,212,865).
5) A compound that is a synthetic intermediate and is represented by the formula:
[Tetrahedron Letters, Vol. 37, No. 51, pp. 9183-9186 (1996)].
6) As compounds having an inhibitory activity of lipid peroxide formation, compounds represented by the formula:
wherein R1 and R2 are the same or different and each is hydrogen, acyl, alkoxycarbonyl, or an aliphatic or aromatic group which respectively may be substituted; R3, R4, and R5 are the same or different and each is hydroxyl that may be acylated, or amino, alkoxy or an aliphatic group, which respectively may be substituted, or two of R3, R4, and R5 may form a carbon homocyclic ring that may be substituted; R6 and R7 are the same or different and each is an aliphatic group that may be substituted, and at least one of R6 and R7 has methylene at the a position; and R8 and R9 are the same or different and each is hydrogen, or an aliphatic or aromatic group, which respectively may be substituted, or salts thereof (EP-A-483772 and JP 5-140142 A).
7) As compounds having bone resorption inhibitory activity, compounds represented by the formula:
wherein R1 is formyl, carbamoyl-lower alkyl, thiomorpholinocarbonyl-lower alkyl, thiomorpholinocarbonyl-lower alkyl S-oxide, pyridylaminocarbonyl-lower alkyl, pyrazolylaminocarbonyl-lower alkyl, triazolylaminocarbonyl-lower alkyl, quinolylaminocarbonyl-lower alkyl that may have one or more appropriate substituents, 3-pyridyl-lower alkylaminocarbonyl-lower alkyl, 4-pyridyl-lower alkylaminocarbonyl-lower alkyl, pyridylethylaminocarbonyl-lower alkyl, pyridyl-lower alkylaminocarbonyl-lower alkyl N-oxide, benzimidazolyl-lower alkylaminocarbonyl-lower alkyl, N-pyridyl-lower alkyl-N-acyl-lower alkylaminocarbonyl-lower alkyl, N-pyridyl-N-lower alkylaminocarbonyl-lower alkyl, lower alkylaminocarbonyl-lower alkyl, di-lower alkylaminocarbonylmethyl, quinolyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, cyano-lower alkyl, di-lower alkylamino-lower alkyl, pyridyl-lower alkyl, triazolyl-lower alkyl, pyrazolyl-lower alkyl that may have one or more appropriate substituents, pyrimidinyl-lower alkyl that may have one or more appropriate substituents, dihydrophthalazinyl-lower alkyl that may have one or more appropriate substituents, oxadiazolyl-lower alkyl that may have one or more appropriate substituents, heterocyclic-lower alkenyl that may have one or more appropriate substituents, lower alkoxyower alkylamino-lower alkyl that may have one or more appropriate substituents, aryl-lower alkylaminocarbonyl-lower alkyl that may have one or more appropriate substituents, arylaminocarbonyl-lower alkyl that may have one or more appropriate substituents, arylthio-lower alkyl that may have one or more appropriate substituents, lower alkyl or an imidazolyl-lower alkyl; R2 is lower alkyl, protected carboxyl or cyano; R3 is halogen or lower alkyl; R4 is hydrogen, nitro or amino; and R5 is halogen, lower alkyl or nitro; provided that, 1) when R1 is methyl, R2 is protected carboxyl or cyano and, 2) when R1 is imidazolylmethyl, R2 is protected carboxyl or cyano, or salts thereof (JP 9-124633 A).
8) As compounds having sodium channel regulating activity, compounds represented by the formula:
wherein each of R1 and R2 is hydrogen atom, lower alkyl that may be substituted or acyl;    each of R3, R4 and R5 is lower alkyl that may be substituted or lower alkoxy that may be substituted, or R4 and R5 together may form a 5- or 6-membered homocyclic ring;    R6 is lower alkyl;    Ar is an aromatic group that may be substituted;    ring A is a 5- to 8-membered nitrogen-containing heterocyclic ring that may be substituted;    X is a lower alkylene that may have substituents;    Y is carbon atom or nitrogen atom;    Za is a group represented by CH2, COCH(R7), OCH(R7), SCH(R7), or N(R10)CH(R7) (wherein R7 is hydrogen atom or an aromatic group that may be substituted; and R10 is hydrogen, a hydrocarbon group that may be substituted, or acyl); Zb is a bivalent aliphatic hydrocarbon group which may have a binding bond or a substituent and may be bonded through oxygen atom, nitrogen atom or sulfur atom; and m is an integer of 1 to 3, or salts thereof (WO 98/08842).
Low-molecular weight compounds, which are excellent in intracerebral permeability and have a neurotrophic factor-like activity and a neurotrophic factor-enhancing activity, are considered to be capable of inhibiting nerve cell death in neurodegenerative diseases such as Alzheimer's disease and the like as well as of improving the symptoms. Then, it has been desired to develop compounds which have a neurotrophic factor-like activity and/or a neurotrophic factor-enhancing activity and, furthermore have excellent pharmacological activities such as a protecting activity of nerve cells by inhibiting cytotoxicity of β-amyloid, or a protecting activity of nerve cells from toxicity of a factor causing nerve cell death, and the like, thereby being useful for pharmaceuticals such as prophylactic and therapeutic drugs of neurodegenerative diseases, and the like.